Psych 3102
Lecture 5
Extensions of Mendel
- continued
Multiple alleles
• where more than two alleles
are present for the trait in
the population
Example: ABO blood group
system in humans
antigen = on surface of red blood
cells
antibody = present in blood plasma
antigen A
+ antibody A
agglutination
(clumping of red cells)
Frequencies of blood
group alleles vary
across populations.
Why?
- resistance to disease
eg. cholera
I = blood group locus
A,B,O are alleles at that locus
IA and IB are co-dominant
IO is recessive to both IA and IB
Can a group A mother have a group O child
with a group B father?
IAIO x IBIO
P
F1
Phenotypes
IAIB
IAIO
IBIO
IOIO
AB
A
B
O
Allelic interactions
- between alleles at one locus
•
complete dominance
- allele is expressed in the phenotype when present in heterozygous condition
example: HD allele
•
recessive
- allele has be present in homozygous condition to show phenotypic expression
example: PKU allele
•
codominance
- both alleles at a locus are expressed in the phenotype
example: AB blood group alleles
•
incomplete dominance
- heterozygote shows intermediate phenotype, full effects
of ‘dominant’ allele are not shown
example: chickens ‘Andalusian blue’ phenotype
horses ‘Palamino’ phenotype
humans familial hypercholesterolemia
haploinsufficiency – 1 copy of wild type allele not enough to
produce wildtype phenotype
Incomplete
dominance in
snapdragons
Gene interactions
- nonallelic interactions
Phenotype is result of complex, integrated pattern of
reactions under control of more than one gene and the
environment.
1.
-
Epistasis (true non-allelic interaction)
expression of a single trait depends on interaction between 2 or more
genes
why is this different from describing the trait as being polygenic?
examples:
comb shape in chickens depends on genotype at 2 unlinked loci (P and R)
Phenotypes
Genotypes
rrpp
R-P-
rrP-
R-pp
(1 : 9 : 3 : 3 in F2)
behavioral example:
anorexia nervosa (AN)
allelic variants of
MAOA
5HTT
NET
genes
Genotype
MAOA risk allele
5HTT alleles
NET risk allele
Risk of AN
slight increase
no effect
x 2 increase
MAOA + 5HTTrisk alleles
x 8 increase
epistasis (non-additive effect)
MAOA + NET risk alleles
slightly more than x 2
no interaction (additive effect)
Important note: results like this often fail to replicate, so whether this is a
real effect or not is uncertain
Epistasis between neurochemical gene
polymorphisms and risk for ADHD
2. Pleiotropy
- a single allele has multiple, correlated phenotypic effects
Sometimes produces heterozygous advantage
(hybrid vigor,overdominance)
- enables an otherwise deleterious recessive allele to survive
in the population at unexpectedly high levels
examples: cystic fibrosis (cholera)
sickle cell disease (malaria)
congenital deafness (dysentery)
• Sickle cell disease
pleiotropic effects across body
point mutation: 6th amino acid in 146 amino acid chain
glu
val - causes red cells to be misshapen
Heterozygous advantage:
resistance to malaria
Sickle cell allele is usually indicated as
recessive
Can the sickle cell allele be completely
recessive?
Analysis of Hb S/haplotype combinations indicates that the mutation must have occurred at least five times. Four
are found predominantly in Africa and are designated Bantu, Benin, Senegal, and Cameroon. A fifth is found in
the populations of India and Saudi Arabia in which the sickle cell gene occurs. The Hb S allele in Sicily and
other Mediterranean areas occurs with the Benin haplotype, which is otherwise very rare there. This suggests an
African origin for the Mediterranean alleles.
There is some difference in severity of sickle cell disease also associated with haplotypes. Persons
homozygous for the Arabian haplotype are least severely affected and those with the Bantu haplotype are the
most severely affected. Because the Hb S mutation does not differ among the haplotypes, it is likely that
regulatory elements in the b-globin complex vary, perhaps resulting in more or less fetal hemoglobin that
interferes with sickling.
The diagnosis of homozygosity for Hb S is readily accomplished by gel electrophoresis of red cell lysates from
blood of newborns or adults. Examination of Hb in fetal red cells cannot be used routinely for diagnosis because
of the low production of b-globin during this period. Direct examination of DNA has made prenatal diagnosis
possible, however. Most earlier procedures were based on the fact that the DNA sequence for codons 5 to 7 is
5′-CCTGAGGAG-3′ in the case of Hb A and 5′ -CCTGTGGAG-3′ for Hb S. The restriction enzyme MstII cleaves
at the sequence CCTNAGG, which is present in Hb A but not in Hb S. Thus the restriction fragment patterns will
differ for the two alleles. The difference can be observed using a Southern blot with an appropriate b-globin
probe. Several variations on polymerase chain reaction (PCR) amplification of the altered DNA segment have
also been developed. These have the advantage of requiring minute quantities of DNA, such as single cells
from an in vitro-fertilized 8-cellembryo or from rare fetal cells in the maternal circulation.
Effective treatment of sickle cell disease has yet to be developed. Current approaches have been directed
toward increasing the level of fetal Hb, which interferes with sickling. Hydroxyurea increases fetal Hb and has
some beneficial effect on sickling, but the levels required and the uncertain long term effects have been
problems. Nevertheless, it is the treatment of choice at present. Bone marrow replacement should be effective
but generates its own major problems.
PKU allele shows pleiotropic effects
point mutation causes non-functional enzyme and inability to
metabolize phenylalanine, subsequent brain damage
tyrosine normally produced from phenylalanine
tyrosine used to produce thyroxine
pleiotropic effects of PKU allele :
fair hair blue eyes
epinephrin
melanin
3. Penetrance
not everyone with a particular genotype shows the expected
phenotype
dominant allele – penetrance = frequency with which it
expresses itself in the phenotype, as percentage
Anything less than 100% = low (or incomplete) penetrance
Examples:
fragile-X mutation - X-linked dominant with 50%
penetrance in females
Huntington allele – penetrance is age-dependent
BRCA-1 - major risk factor allele for breast cancer, agedependent penetrance
37% by age 40
w/out allele = 0.4%
66% by age 55
3%
85 % by age 80
8%
4. Expressivity
degree to which penetrant
allele expresses itself in
phenotype
Examples:
osteogenesis imperfecta
autosomal dominant
100% penetrant since all who carry
allele show blue sclera
phenotype, other effects vary
fragile-X syndrome
X-linked dominant, 50% penetrance
males more severely effected than
females, but expression varies in
both sexes
5. Internal environment
factors that can change expression of
genes:
age
Huntington allele Duchenne muscular dystrophy
male-pattern baldness
gender
sex-linked traits alleles on X or Y chromosome
sex-limited traits alleles NOT on sex chromosome
but affected by genes on sex chromosomes
(epistasis)
Baldness sex-limited trait
50% male population, small number of women
androgenic alopecia = male-pattern baldness, most
common cause
2 major genes
androgen receptor on X (X-linked) x 3.3 risk
transcription factor region on 20p
x 1.6 risk
both risk alleles (14% of men)
x 7 risk
epistasis
6. External environment
environmental factors that can change
gene expression:
temperature
coat color in Himalayan rabbits
sex-determination in crocodilians
environmental chemicals
phenocopies non-hereditary phenotypic
modifications that mimic the effect of genes
German measles/hereditary deafness
thalidomide/phocomelia
Accutane/congenital deformities
interactions
genotype x environment interactions where effect
of genotype depends on environment (& vice-versa)
effect of diet on PKU
effect of smoking/a-1-antitrypsin gene
effect of diet on coat color in mice
Epigenetics
possible mechanism for GxE
- gene expression is altered (eg. by methylation)
- phenotype is altered
- genotype is unchanged
Example of an environmental factor changing gene
expression : - coat color in agouti mice
pregnant female mice fed diet with supplements of vit B12,
folic acid, & choline had offspring with agouti coats
pregnant female mice fed diet without supplements had
offspring with yellow coats + offspring had tendency to
diabetes, heart disease, obesity
extra nutrients turned down expression of agouti gene,
which has pleiotropic effects on appetite and metabolism
as well as effecting coat color.
Research Highlight
Nature Reviews Genetics 12, 80 (February 2011) | doi:10.1038/nrg2941
Epigenetics: Dad's diet lives on
Two recent studies in rodents show that unhealthy paternal diets can reprogramme gene
expression in offspring, implicating epigenetics in these transgenerational effects.
Ng and colleagues fed male rats a high-fat diet and looked for effects in their adult female
offspring, which were fed a normal diet. These daughters had normal body fat but showed
signs of pancreatic β-cell impairment and altered expression (as compared to controls) of 642
genes that are involved in pathways related to insulin regulation and glucose metabolism. The
gene with the greatest alteration in expression was interleukin-13 receptor-α2 (Il13ra2), which
is implicated in regulating pancreatic cell function. Interestingly, DNA methylation at a
cytosine residue close to the Il13ra2 transcriptional start site was reduced in these females.
Carone and colleagues looked at the effect of a paternal low-protein diet in mice. Offspring of
both sexes showed altered gene expression compared to controls, including genes involved
in fat and cholesterol biosynthesis, consistent with physiological differences in these mice.
Modest changes in DNA methylation were seen at many sites, including a reproducible
change close to the Ppara gene, which encodes peroxisome proliferator-activated receptor-α,
a regulator of lipid metabolism.
Although there is increasing evidence for effects of parental environment in offspring, these
studies add to just a handful of cases in which the molecular basis has been at least partly
elucidated. Clearly, the role of epigenetics in such transgenerational effects will be an
important focus of future studies.